The aims of the program project are to study the mechanism of contraction of cardiac muscle. The focus is on fundamental properties, i.e., on the manner in which force is generated and regulated. The investigators come from various disciplines including physiology, bioengineering, biochemistry, biostructure and pharmacology. The majority of them are senior investigators with considerable experience and a history of collaboration. Their areas of expertise will be combined in a multidisciplinary, highly interactive effort to study the fundamentals of contraction in the heart. Several specific issues are to be investigated using complementary methodologies. In Project I, the phenomenon of stepwise sarcomere shortening will be pursued using several optical and mechanical techniques. The question of whether stepwise shortening is associated with thick filament shortening is investigated in Project II, using both the freeze-fracture method and optical imaging of the striations. In Project III, myofilament activation will be studied using a new fluorescent probe to measure bound calcium. This is closely related to Project IV, in which activation and other factors are considered as possible mechanisms underlying Starling's Law of the Heart; skinned and intact preparations will be studied. In Project V, the effect of history on contractile performance is considered with methods including those in each of the first four projects. Finally, in Project VI, the subcellular disposition of calcium in various compartments of heart cells will be investigated using the X-ray microanalysis method. There will be four core facilities in support of these research activities: Core A - Administrative; Core B - Computer Programming; Core C - Electron Microscopy; and Core D - Instrumentation. These facilities will be used broadly by the investigators, thereby serving as an additional focal point of interaction.